Early Life Estrogenicity and Mammary Cancer Risk. While the timing of estrogen exposures has profound and often opposing effects on breast cancer suscepfibility, the molecular changes and programming that are altered by these exposures are almost entirely unknown. Dr. Hilakivi-Clarke and her team will focus on identifying key transcription factor-based signaling associated with increased mammary cancer risk in the mammary glands of rodents exposed to an elevated estrogenic environment in utero. We will determine the effects of these exposures on altering the sensitivity of the adult gland to E2, and on the endocrine responsiveness of mammary tumors arising in these glands. Data from these studies will be used to build computational models of ER-driven signaling associated with the effects of estrogens on increasing mammary gland susceptibility to neoplastic transformation and on endocrine responsiveness of mammary tumors. These data will also provide and unique powerful insights into the modeling in Projects 1 and 2.